New Chemical Entities Research Articles

A novel series of substituted 1,2,3-triazoles as cancer stem cell inhibitors: Synthesis and biological evaluation.

An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs), contributing majorly to the chemoresistance and tumor relapse, seem to the main culprits. In the present investigation, new chemical entities (NCEs) belonging to four novel chemical series (A: 4'-allyl-2'-methoxyphenoxymethyl-1,2,3-triazoles; B: 4'-acetamidophenoxymethyl-1,2,3-triazoles; C: naphthalene-1'-yloxymethyl-1,2,3-triazoles, and D: naphthalene-2'-yloxymethyl-1,2,3-triazoles) were synthesized via Copper (I)-catalyzed alkyne-azide cycloaddition reaction and evaluated for in vitro anticancer activity. A total of 30 NCEs (39-68) were screened at 10 μM concentration in cell viability assay against cancer cell lines such as breast (MDA-MB-231), prostate (PC-3), glioma (U87 MG), along with cervical (SiHa) and lung (A549). The NCEs from Series C (56-60) and D (61-68) were more potent than those in Series A (39-45) and Series B (46-55) at the tested concentration. Furthermore, NCEs with >80% inhibition at 10 μM were evaluated for dose response. A total of five NCEs, 48, 56, 61, 65 and 66, were further assessed in soft-agar assay and found to be relatively potent (IC50 < 10 μM). Finally, the hits were screened in sphere assay to identify potential CSC inhibitors against mammospheres (MDA-MB-231) and prostatospheres (PC-3). More so, the hits were also evaluated to understand in vitro cytotoxicity against normal cells using mouse embryonic fibroblast cell line (NIH/3T3) and human peripheral blood mononuclear cells (hPBMCs). Overall, hits 56 and 61 exhibited potent anticancer as well as CSC inhibitory activities with notably less toxicity toward NIH/3T3 and hPBMCs. On the whole, our arduous study led to the identification of potential hits with anticancer and CSC inhibitory activities, with minimal or no toxicity to normal cells.

Current medicines for malaria including resistance issues

Malaria is an old disease and continues to be a major health problem in many countries. In spite of decrement in morbidity and mortality due to malaria, the transmission is still active throughout the world. Hence, appropriate treatment is needed to handle malaria in addition to preventive measures. However, unavailability of new drugs and the occurrence of resistant Plasmodium strains toward many conventional antimalarial drugs including artemisinins are the major obstacles in combating malaria infection. Thus, experts from all directions of our planet are in search of novel compounds, and many new chemical entities, such as artefenomel, ferroquine, KAE609, KAF156, DSM265, methylene blue, MMV39048, DDD107498, SJ733, and MMV253, have been under drug development process. While many agents are in the pipeline, most of them are not able to kill both gametocytes and hypnozoites.

A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis

Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline.

Synthesis and Antibacterial / Anticancer Activities of Compounds Containing Pyrazole Ring Linked to Piperazines

Background: Many pyrazole piperazine derivatives are known to exhibit a wide range, thus being attractive for the drug design and synthesis of interesting class of widely studied heterocyclic compounds. It is therefore necessary to devote continuing effort for the identification and development of New Chemical Entities (NCEs) as potential antibacterial and anticancer agents to address serious health problems. Methods: A series of new compounds containing pyrazole ring linked to a piperazine hydrochloride moiety were synthesized and screened for their antibacterial activity, cytotoxicity of novel scaffolds are described by variation in therapeutic effects of parent molecule. The structure variants were characterized by using a blend of spectroscopic 1H NMR, 13C NMR, IR, Mass and chromatographic techniques. Results: When tested for in vitro antibacterial and anticancer activities, several of these compounds showed good activities. The target compounds 9b, 9a and 9e exhibited a high degree of anticancer activity against human colon cancer cell line Caco-2 and human breast cancer cell line MDAMB231. Further, 9a, 9b, 9d, and 9h showed better activity towards four medically relevant organisms; Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Klebsiella Species compared to CPF. In the present investigation, cheminfomatics tools Molinspiration, 2003 and MolSoft, 2007 for the prediction of insilico molecular properties and drug likeness for the target compounds 9a-h was evaluated and positive results were observed. Conclusion: Our study revealed that the molecular framework presented here could be a useful template for the identification of novel small molecules as promising antibacterial/ anticancer agents.

Nano-sizing Crystals: An Exquisite Way of Drug Conveyance

Extensive attempts have been made to decipher the problem associated with the solubility of drugs for maximizing bioavailability at targeted sites. More than 40% NCEs (new chemical entities) emerged through modern technology like high throughput screening, combinatorial chemistry, computer-aided drug design etc. and the drug discovery process has been dramatically accelerated. Fabrication of materials into the nanodimension changes their physical properties which depicts a vivid shift from lab scale optimization studies to scale up focused studies. In addition, this comprehensive review covers physics behind the drug nanocrystals and their properties, different technologies and methods of drug nanocrystal preparation and its stabilization along with theapplication of nanocrystals. This review also covers factors affecting nanoformulations, post-production processing and future prospects.

Translational Modeling Strategies for Orally Administered Drug Products: Academic, Industrial and Regulatory Perspectives.

During non-clinical and clinical development of a new molecular entity (NME), modeling and simulation (M&S) are routinely used to predict the exposure and pharmacokinetics (PK) of the drug compound in humans. The basic methodology and output are generally understood across all functional disciplines. However, this understanding is mostly restricted to traditional methods such as those in simplified kinetic models and void of adequate mechanistic foundation to address questions beyond the observed clinical data. In the past two decades, alternative and more mechanistic methods, particularly for describing absorption, distribution, excretion and metabolism (ADME) of drugs have been developed and applied under the general umbrella of physiologically-based pharmacokinetic (PBPK) methods. Their mechanistic nature gives the ability to ask many other questions which were not traditionally asked and provide some logically and evidenced-based potential answers. Whilst traditional PK methods are mainstream and understood by most scientists, mechanistic absorption models alongside other PBPK approaches are still deemed eclectic, despite making significant strides in the fundamental science as well as regulatory acceptance. On November 3rd, a short course was held at the annual American Association of Pharmaceutical Scientists (AAPS) meeting in San Antonio, Texas. The different talks were tailored to provide a basis or rationale for the subject, introduction to fundamental principles with historical perspective, a critique of the state-of-the-art, examples of successful application of the methods across different phases of the drug development process and the specific standards these mechanistic models should meet to be fully reliable from a regulatory perspective.

PDG38 ASSESSMENT OF GENERIC COMPETITION FOR ORPHAN DRUGS MARKETED IN THE US (1993-2019)

The Orphan Drug Act of 1982 created the orphan designation for drugs for the treatment of rare diseases that affect less than 200 thousand patients in the US. This study evaluated generic competition of orphan and non-orphan new molecular entities approved by the US US FDA in the period 1983-2019. Data for all new molecular entities (NME) and orphan drugs approved by the FDA in the period 1983-2019 were compiled from the USFDA website. The study compared orphan and non-orphan drugs as a percentage of drugs without patent or market exclusivity and generic competition, the number of abbreviated new drug applications (ANDA), and the difference between the approval of a new drug application (NDA) and the first ANDA. Descriptive analysis, linear and logistic regression were conducted using IBM SPSS vs.25. The FDA approved 628 NME in the period 1983-2019 that did not have patent or exclusivity protection as of December 31, 2019. The analysis included 506 (80.1%) that were marketed by December 31, 2019, of which 104 (20.1) were orphan drugs. Generic competition occurred for 65 (62.5%) orphan drugs and 352 (87.6%) non-orphan drugs (p<0.0001). The period from the NDA to the first ANDA approval was 12.7+4.6 years for non-oprhan drugs and 12.2+- 5.6 years for orphan drugs (NS). The number of ANDAs was lower for orphan (7.2+-6.6, median 7) than for non-orphan drugs (15.5+-12, median=11). After controlling for other factors, orphan designation was significantly and negatively associated with generic entry, and the number of ANDAs approved by the FDA. No significant differences in time from NDA to ANDA approval were observed between orphan and non-orphan drugs. Orphan drugs experience less generic competition and have a lower number of generic drugs than non-orphan drugs reducing affordability to essential therapeutic alternatives.

PDG61 TYPES OF ENDPOINTS OF NEW MOLECULAR ENTITIES APPROVED BY THE FDA: THE INCREASING IMPORTANCE OF PATIENT-REPORTED OUTCOMES

Clinical outcome assessments (COAs) are measurements that represent aspects of a patient’s health status and are used to evaluate clinical benefit when developing a therapy for a disease or condition. Types of COAs include patient-reported outcomes (PROs), clinician-reported outcomes (ClinROs), and performance outcomes (PerfOs). Given the increasing emphasis on patient-centered care, PROs have become especially important in recent years. The objective of the current study was to assess the use of different endpoint types, particularly PROs, in confirmatory studies of new molecular entities (NMEs) approved from 2016-2019. A descriptive analysis was conducted utilizing data from NMEs approved by the Food and Drug Administration (FDA) for treatment between January 1, 2016 and December 31, 2019. FDA approval drug labels were reviewed to identify the drug indication and endpoints of confirmatory studies. ICD-10 codes were used to classify the disease type, and the primary and secondary endpoints were classified based on the type of endpoint (survival, biomarker, ClinRO, ObsRO, PRO, PerfO). A total of 122 NMEs were approved by the FDA for treatment during 2016-2019. Biomarkers (either alone or in conjunction with other endpoint types, allowing for summation of >100%) were the most common primary endpoint (56.2%), followed by ClinROs (48.8%), PROs (24.8%), survival (14.9%), and PerfOs (5.8%). PROs as a primary endpoint were most prominent in pivotal studies related to nervous system diseases (57.1%). The use of PROs as a primary endpoint has almost doubled from what was previously reported in 2011-2015 (13.2%; Gnanasakthy 2016). Although the majority of pivotal studies were largely based on biomarkers and ClinROs in the past 4 years, PROs have seen a sharp increase in use as the primary endpoint in pivotal studies, almost doubling from 2011-2015 to 2016-2019, indicating the rising importance of the patient perspective in trial outcomes.

Synthetic Approaches to New Drugs Approved during 2018.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for the first time globally in 2018.

Liver Enzyme Elevations in Plasmodium falciparum Volunteer Infection Studies: Findings and Recommendations.

.Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5–5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.

A Review on Drug Combination Strategy for Pharma Life Cycle Management

Discovering a new drug and developing it to the clinic is a, time-consuming and expensive process. A successfully developed patented drug enjoys market exclusivity which provides an opportunity to recoup the R&D expenses. Market competition with similar drugs from other companies, patent cliff and entry of generics present a threat to revenue generation. Successful pharma companies employ suitable Life Cycle Management (LCM) strategies, timed to expand the clinical utility of the drug and boost the revenues through new market exclusivities. Drug combination is one such strategy adopted to add therapeutic value and enhance the commercial life of a drug. In this article, we review drug combination as a Life Cycle Management (LCM) strategy adopted for the US Food and Drug Administration (FDA) approved drugs. We analysed New Molecular Entity (NME) approved by the FDA in the decade of 2001-2010 in four therapeutic areas of oncology, central nervous system, alimentary canal and metabolism and cardiovascular. The life cycle of these NMEs was tracked till 2019 focusing on fixed dose and free dose combination. We present case studies on sitagliptin and everolimus belonging to therapeutic areas metabolism and oncology, respectively, and critically discuss the life cycle of these two drugs. Through the presentation of the clinical utility and revenue generated for the drug combinations, we provide insights into drug combination as a life cycle management strategy.

Reconstituted Human Organ Models as a Translational Tool for Human Organ Response: Definition, Expectations, Cases, and Strategies for Implementation in Drug Discovery and Development.

Recent progress in the fields of tissue engineering, micro-electro mechanical systems, and materials science have greatly improved cell culture systems, which were traditionally performed in a static two-dimensional manner. This progress has led to a number of new cell culture concepts represented by organ-on-a-chip, three dimensional (3D)-tissues, and microphysiological systems, among others. In this review, these culture models are categorized as reconstituted human organ models, which recapitulate human organ-like structure, function, and responses with physiological relevance. In addition, we also describe the expectations of reconstituted organ models from the viewpoint of a pharmaceutical company based on recent concerns expressed in drug discovery and development. These models can be used to assess the pharmacokinetics, safety and efficacy of new molecular entities (NMEs) prior to clinical trials. They can also be used to conduct mechanistic investigations of events that arise due to administration of NMEs in humans. In addition, monitoring biomarkers of organ function in these models will aid in the translation of their changes in humans. As the majority of reconstituted human organ models show improved functional characteristics and long-term maintenance in culture, they are valuable for modeling human events. An example is described using the three-dimensional bioprinted human liver tissue model in this article. Implementation of reconstituted human organ models in drug discovery and development can be accelerated by encouraging collaboration between developers and users. Such efforts will provide significant benefits for delivering new and improved medicines to patients.

Drug-target Interaction Prediction by Metapath2vec Node Embedding in Heterogeneous Network of Interactions

Drug discovery is a complicated, time-consuming and expensive process. The cost for each new molecular entity (NME) is estimated at $1.8 billion. Furthermore, for a new drug to be FDA approved it often takes nearly a decade and approximately 20 new drugs being approved by the US Food and Drug Administration (FDA) each year. Accurately predicting drug-target interactions (DTIs) by computational methods is an important area of drug research, which brings about a broad prospect for fast and low-risk drug development. By accurate prediction of drugs and targets interactions scientists can scale-down huge experimental space and reduce the costs and help to faster drug development as well as predicting the side effects and potential function of new drugs. Many approaches have been taken by researchers to solve DTI problem and enhance the accuracy of methods. State-of-the-art approaches are based on various techniques, such as deep learning methods-like stacked auto-encoder-, matrix factorization, network inference, and ensemble methods. In this work, we have taken a new approach based on node embedding in a heterogeneous interaction network to obtain the representation of each node in the interaction network and then use a binary classifier such as logistic regression to solve this prominent problem in the pharmaceutical industry. Most introduced network-based methods use a homogeneous network of interactions as their input data whereas in the real word problem there exist other informative networks to help to enhance the prediction and by considering the homogeneous networks we lose some precious network information. Hence, in this work, we have tried to work on the heterogeneous network and have improved the accuracy of methods in comparison to baseline methods.

Combining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized guinea pig assay

Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig (CVGP) assay for new chemical entities (NCEs) and; 2) Determine if a translational pharmacokinetic/pharmacodynamic (tPKPD) model can improve the predictive capacity. In silico simulations for NCEs were performed using a population of human ventricular action potential (AP) models. PatchXpress® (PX) or high throughput screening (HTS) ion channel data from respectively n = 73 and n = 51 NCEs were used as inputs for the in silico population. These NCEs were also tested in the CVGP (n = 73). An M5 pruned decision tree-based regression tPKPD model was used to evaluate the concentration at which an NCE is liable to prolong the QTc interval in the CVGP. In silico results successfully predicted the QTc interval prolongation outcome observed in the CVGP with an accuracy/specificity of 85%/73% and 75%/77%, when using PX and HTS ion channel data, respectively. Considering the tPKPD predicted concentration resulting in QTc prolongation (EC5%) increased accuracy/specificity to 97%/95% using PX and 88%/97% when using HTS. Our results support that human-based in silico simulations in combination with tPKPD modeling can provide correlative results with a commonly used early in vivo safety assay, suggesting a path toward more rapid NCE assessment with reduced resources, cycle time, and animal use.

Assessment of contribution of BCRP to intestinal absorption of various drugs using portal-systemic blood concentration difference model in mice.

Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P‐glycoprotein (P‐gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco‐2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the correlation between the in vitro AQ for BCRP and in vivo contribution of BCRP on drug absorption, we evaluated the oral absorption of various compounds by portal‐systemic blood concentration (P‐S) difference method in wild‐type (WT), Bcrp(−/−), and Mdr1a/1b(−/−) mice. In addition, we also calculated a rate of BCRP contribution (Rbcrp). Ciprofloxacin and nitrofurantoin showed the low Rbcrp value (0.05 and 0.15), and their apparent fractions of intestinal absorption in WT mice were 46.5% and 63.7%, respectively. These results suggest that BCRP hardly affects their intestinal absorption in mice. On the other hand, the apparent fraction of intestinal absorption of topotecan and sulfasalazine was significantly lower in WT mice than in Bcrp(−/−) mice. Moreover, their Rbcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo Rbcrp calculated in this study was almost comparable to in vitro AQ obtained from Caco‐2 permeability study. This study provides useful concepts in assessing the contribution of BCRP on intestinal absorption in drug discovery and development process.

P518 Ulcerative colitis drug development success rates are higher than the industry average

Abstract Background Given the increasing costs of drug development, coupled with low success rates, there is a need to both develop better predictive models and elucidate causes of failure. However, for indications such as ulcerative colitis, a baseline does not presently exist. In this paper, we review trends in drug development and establish a baseline for ulcerative colitis. Methods We used BiomedTracker to obtain information about the number of compounds, which were in development for ulcerative colitis between 2005 and 2018. We counted the number of compounds, which had reached a particular phase, had been discontinued during this phase, had successfully passed it or had been still in this phase. Success rates were derived for the different phases of drug development for all 73 candidate drugs and divided by type of molecule and type of company. A success rate was calculated by dividing the number of drugs successfully completing a particular phase by the sum of the number of drugs which were discontinued during this phase and the number of compounds that completed positively a phase. The likelihood for approval (LOA) for each phase was calculated by multiplying the success rate for the respective phase with the success rates of next stages of development. Results The success rate in phase I was 96 %, in phase II 53 % and in phase III 76%, while the respective LOA was 0.39, 0.4 and 0.76. Table 1 demonstrates the success rates and LOA by type of compound(New molecular entity (NME), Biologic, non-NME) and type of company (big, mid-size, emerging). Conclusion The general industry success rates and LOA for phase I is 64%, for Phase 2 30%, and for phase 3 60% while the LOA from phase I is 10%. These data are published by Michael Hay and co-authors in Nature in January 2014. The success rates in UC drug development are therefore higher than the overall industry success rates.

FDA Reported Use of Patient Experience Data in 2018 Drug Approvals

Background“Patient experience data” (PED) refers to the systematic collection of meaningful data relating to the experiences, perspectives, needs, and priorities of patients. PED can augment traditional clinical trial data in the FDA’s review of product applications. Section 3001 of the 2016 21st Century Cures Act requires the FDA to make a public statement about the PED considered in the approval of a drug application. Here, we present one of the first assessments of PED consideration during drug application approval, as reported by the FDA under Sec. 3001 of the Cures Act.MethodsFDA reported use of PED in the Review Documentation of the 59 new molecular entities (NMEs) approved in 2018 were collected, indexed, and cross-referenced against information regarding FDA review and product regulatory designation. The data reported in the PED tables were quantitatively described and visualized.ResultsOf the 59 approved NMEs in 2018, 48 include a table that summarized whether PED was or was not used during the FDA drug review. Thirty-four of those 48 approvals (70.8%) reported using PED in the drug review. Patient-reported outcomes(PROs) represented the most significant source of PED and were used in 60.4% of approved drug reviews. Additional findings, including PED use by FDA review division and by FDA regulatory designation, are described.ConclusionsThis assessment is a first step to better understanding how FDA considers PED in regulatory decision making. This analysis should help develop a baseline regarding FDA use of PED and may inform decisions to ensure patients’ experiences are adequately heard in future drug development.

Analyzing Upward Deviation of Actual vs Predicted Drug Sales in Japan for a Reasonable Drug-Pricing Policy.

Predictions of drug sales play an important role in setting drug prices in Japan, where drug prices are highly regulated. One of 2 primary Japanese drug-pricing methodologies-the cost calculation method- refers extensively to the prediction of drug sales in establishing drug prices. Deviations from predicted sales can induce disproportionate drug prices and unexpected pharmaceutical expenditures. This study aimed to estimate the upward deviation of actual sales from predicted sales and to explore the predictors of such upward deviation. Estimates of upward deviation in 2015 were produced for new molecular entities (NMEs) approved in 2006-2015. To identify the predictors associated with upward deviation through binary logistic regression analyses, sales within 3 years of launch and in the predicted year in which peak sales would be reached were used. Estimated upward deviation was more than 1220 billion yen in 2015 for the targeted drugs. Drugs priced by the cost calculation method or by obtaining additional indications were significantly more likely to show an upward deviation from predicted peak sales. There is substantial upward deviation between actual and predicted drug sales in Japan. So long as drug sales predictions are used in drug price calculations, a flexible repricing system is needed to buffer unexpected pharmaceutical expenditures.

Phytomolecules against bacterial biofilm and efflux pump: an in silico and in vitro study

Antibiotic resistance is a global threat whose incidences are increasing day by day worldwide. Thus, there is a need for new chemical entities (NCEs) or exploration of existing molecules against these types of infections. In the current investigation, we have tested the inhibitory potential of four different phytomolecules (berberine, gallic acid, piperine, and rutin) against bacterial biofilm and efflux pumps by using in-silico and in-vitro techniques. The phytomolecules (berberine, piperine, and rutin) except gallic acid have shown good interaction towards biofilm and efflux pump proteins. Further, In-vitro studies have also shown the good inhibitory effect of tested phytomolecules (berberine, rutin, and piperine) against bacterial biofilm formation and efflux pumps. In conclusion, berberine, piperine, and rutin could be the promising antibacterial candidates, particularly against resistant bacterial strains.Communicated by Ramaswamy H. Sarma

Photocatalysis as a Tool for in Vitro Drug Metabolism Simulation: Multivariate Comparison of Twelve Metal Oxides on a Set of Twenty Model Drugs

The constant development in the area of medicinal substances on the market and their subsequent progress in the field of drug analysis has become one of the reasons for the search for alternative, cheaper, and faster methods to determine the metabolism pathways of new molecular entities (NMEs). The simulation of transformation processes using photocatalysis is considered to be one of the promising methods. Although its effectiveness has been proven, the research has so far focused especially on titanium dioxide, while a more accurate comparison of the suitability of different photocatalysts in terms of their use in drug metabolism studies has not been performed. For this purpose, a set of twelve metal oxides was prepared and their photocatalytic efficiency in the direction of drug metabolism mimicking was checked on a model mixture of twenty medicinal substances differing both in chemical structure and pharmacological properties. Incubation with human liver microsomes (HLMs) was used as the reference method. The metabolic profiles obtained with the use of LC-MS analysis were compared using multidimensional chemometric techniques; and the graphic presentation of the results in the form of PCA plot and cluster dendrogram enabled their detailed interpretation and discussion. All tested photocatalysts confirmed their effectiveness. However, the exact outcome of the study indicate advantage of the WO3-assisted photocatalysis over other metal oxides.